Quantifying Sex-and-Age-Related Differences in Antiretroviral Exposure and Adverse Effects in the MACS/WIHS Combined Cohort Study

MACS/WIHS 联合队列研究中抗逆转录病毒药物暴露和不良反应的性别和年龄相关差异的量化

• 批准号: 10161378
• 负责人: Julie Brumer Dumond
• 金额: $ 78.4万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-09 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10161378
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Adverse drug event; Adverse effects; Adverse event; Affect; African American; Age; Aging; Analytical Chemistry; Anti-Retroviral Agents; Automobile Driving; Biological Aging; Biological Markers; Biological Specimen Banks; Body Weight; CD4 Positive T Lymphocytes; Cell Count; Characteristics; Clinical; Clinical Pharmacology; Clinical Trials; Clinical effectiveness; Cohort Studies; Color; Complex; Data; Diagnostic; Drug Approval; Drug Evaluation; Drug Exposure; Drug Kinetics; Drug Modelings; Enrollment; Epidemic; Exposure to; Female; Genetic; Goals; HIV; HIV-1; Hispanics; Hormonal; Hour; Immunologics; Incidence; Insulin Resistance; Integrase; Integrase Inhibitors; Investigation; Knowledge; Laboratories; Latina; Measures; Metabolic; Methods; Modeling; Morbidity - disease rate; Outcome; Participant; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Phase; Phase III Clinical Trials; Phenotype; Plasma; Plasma Cells; Population; Population Heterogeneity; RNA; Recovery; Regimen; Research; Risk; Risk Estimate; Risk Factors; Sampling; Site; Span 20; Specimen; Tenofovir; Testing; Toxic effect; Validation; Viral; Visit; Waist-Hip Ratio; Weight Gain; Woman; Work; adverse event risk; age effect; age related; antiretroviral therapy; base; cohort; drug clearance; ethnic diversity; evidence base; evidence based guidelines; experience; frailty; high risk; improved; individual variation; inhibitor/antagonist; interest; men; mortality; older patient; patient subsets; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; precision medicine; prospective; response; sex; socioeconomics; tool; Acquired Immunodeficiency Syndrome; Adult; Adverse drug event; Adverse effects; Adverse event; Affect; African American; Age; Aging; Analytical Chemistry; Anti-Retroviral Agents; Automobile Driving; Biological Aging; Biological Markers; Biological Specimen Banks; Body Weight; CD4 Positive T Lymphocytes; Cell Count; Characteristics; Clinical; Clinical Pharmacology; Clinical Trials; Clinical effectiveness; Cohort Studies; Color; Complex; Data; Diagnostic; Drug Approval; Drug Evaluation; Drug Exposure; Drug Kinetics; Drug Modelings; Enrollment; Epidemic; Exposure to; Female; Genetic; Goals; HIV; HIV-1; Hispanics; Hormonal; Hour; Immunologics; Incidence; Insulin Resistance; Integrase; Integrase Inhibitors; Investigation; Knowledge; Laboratories; Latina; Measures; Metabolic; Methods; Modeling; Morbidity - disease rate; Outcome; Participant; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Phase; Phase III Clinical Trials; Phenotype; Plasma; Plasma Cells; Population; Population Heterogeneity; RNA; Recovery; Regimen; Research; Risk; Risk Estimate; Risk Factors; Sampling; Site; Span 20; Specimen; Tenofovir; Testing; Toxic effect; Validation; Viral; Visit; Waist-Hip Ratio; Weight Gain; Woman; Work; adverse event risk; age effect; age related; antiretroviral therapy; base; cohort; drug clearance; ethnic diversity; evidence base; evidence based guidelines; experience; frailty; high risk; improved; individual variation; inhibitor/antagonist; interest; men; mortality; older patient; patient subsets; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; precision medicine; prospective; response; sex; socioeconomics; tool

ABSTRACT The long-term objective of the proposed work is to provide evidenced-based recommendations for minimizing metabolic adverse events, particularly weight gain, in a diverse population of people living with HIV (PLWH) by identifying and quantifying variability in drug exposure that may increase risk in patient subgroups. We will consider a broad array of modifying factors of drug exposure, including demographic characteristics, prior laboratory values, body anthropometrics, frailty phenotype, and pharmacogenomics. Our focus is on the integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG) and bictegravir (BIC), as well as tenofovir alafenamide (TAF). The MWCCS includes diverse PLWH underrepresented in Phase III clinical trials and thus, in the sponsor-developed population pharmacokinetic models of the drug. In AIM 1, we will enroll diverse PLWH from four MWCCS sites to collect pharmacokinetic data and further refine the knowledge of factors that influence DTG, BIC, and TAF pharmacokinetics. Drug concentrations will be measured in blood plasma and peripheral blood mononuclear cells (TAF only) in the UNC Center for AIDS Research Clinical Pharmacology and Analytical Chemistry Laboratory (CFAR CPAC). Nonlinear mixed effects models will be used to develop a comprehensive PK model for each drug of interest. Using these models, then, in AIM 2, we will retrospectively measure drug concentrations in repository specimens (using the same methods and laboratory as AIM 1, and predict drug clearance in men and women from initiation of DTG, BIC, and/or TAF. These drug clearances, predicted for multiple visits per participant, will then be analyzed as the predictors of body weight gain, increased waist to hip ratio, and increased insulin resistance (as measured by HOMA-IR) over the course of treatment on the drug of interest, with multiple measures of drug exposure. The hypothesis is that those PLWH with higher drug exposure (via slower drug clearance) will be more likely to experience the metabolic adverse events of these drugs. Upon completion, we expect to have the underpinnings of a model-based risk estimator developed for further prospective validation.

抽象的 拟议工作的长期目标是提供基于证据的建议，以最大程度地减少 代谢不良事件，尤其是体重增加，在艾滋病毒（PLWH）的各种各样的人群中 识别和量化药物暴露的变异性，可能会增加患者亚组的风险。我们将 考虑一系列广泛的药物暴露因素，包括人口统计学，先验 实验室价值，人体人类测量学，脆弱的表型和药物基因组学。我们的重点是 整合酶链转移抑制剂（Instis）DoluteGravir（DTG）和Bictegravir（BIC）以及Tenofovir Alafenamide（TAF）。 MWCC在III期临床试验中包括多种多样的PLWH，因此 在赞助商开发的该药物的药代动力学模型中。在AIM 1中，我们将注册多样化的PLWH 从四个MWCC站点收集药代动力学数据，并进一步完善有关影响因素的知识 DTG，BIC和TAF药代动力学。药物浓度将在血浆和周围测量 UNC AIDS研究中心研究临床药理学和分析中的血液单核细胞（仅TAF） 化学实验室（CFAR CPAC）。非线性混合效应模型将用于开发全面 每种感兴趣药物的PK模型。然后，使用这些模型，在AIM 2中，我们将回顾性测量药物 存储库标本的浓度（使用与AIM 1相同的方法和实验室，并预测药物 启动DTG，BIC和/或TAF的男女清除。这些药物清除，预计 然后，每个参与者多次访问，然后将分析为体重增加的预测因子，腰部增加到臀部 比率和增加的胰岛素耐药性（通过HOMA-IR测量）在治疗过程中 兴趣，有多种药物暴露量度。假设是那些具有较高药物暴露的PLWH （通过较慢的药物清除率）将更有可能体验这些药物的代谢不良事件。之上 完成，我们期望开发基于模型的风险估计器的基础，以进一步 潜在验证。